Cycloadditions are powerful reactions that can build complex structures rapidly from simple starting materials. This proposal focuses on developing new cycloadditions of the highly reactive, anti-aromatic species, cyclobutadiene. The significant strain that is captured in these unique transformations provides extraordinarily concise entries into nontrivial, biologically active natural products and derivatives, as well as unique small molecule libraries. Specifically, intramolecular cycloadditions between cyclobutadiene and a variety of new reaction partners such as trienes, imines, and carbonyl groups will be examined. These new cycloadditions will lead to highly functionalized, novel cyclobutene-containing carbo- and heterocyclic ring systems. The inherent value of these transformations becomes apparent when the cycloadducts are employed in other unique complexity building and ring fragmentation strategies. It is a synergistic combination of new reactions that provides access to numerous biologically active, complex medium ringcontaining compounds in roughly half the number of chemical transformations that were previously required to generate such highly complex targets. Relevance: Developing new and more powerful reactions and molecule building strategies will lower the cost of preparing current and future pharmaceutical agents. In addition, the new reactions will offer rapid and convenient access to complex, biologically active compounds that were once considered too costly for study or use in pharmacutical applications. Likewise, the cycloaddition provides access to libraries of untested, completely novel structures that may uncover unique opportunities in drug discovery and Chemical Biology.